Methods for buffer stabilized aqueous deacylation

ABSTRACT

The present invention relates to novel methods for stabilizing aqueous deacylation, via use of buffers in the production of sucralose. The present invention provides a process for producing sucralose from an acyl-sucralose compound whereby the acyl-sucralose compound is deacylated in the presence of a buffering agent, which stabilizes the pH of the feed mixture and decreases the accumulation of undesired anhydro compounds. Further, the present invention provides a process whereby the acyl-sucralose compound is deacylated directly either prior to or after removal of the tertiary amide reaction vehicle from the neutralized chlorination feed mixture. An aqueous solution of sucralose including salts and other compounds is produced, from which sucralose is recovered by extraction and purified by crystallization.

FIELD OF THE INVENTION

The present invention relates to novel methods for stabilizing aqueousdeacylation, via use of buffers, in the production of sucralose. Thepresent invention provides a process for producing sucralose from anacyl-sucralose compound whereby the acyl-sucralose compound isdeacylated in the presence of a buffering agent, that stabilizes the pHof the feed mixture and decreases the accumulation of undesired anhydrocompounds. Further, the present invention provides a process whereby theacyl-sucralose compound is deacylated directly either prior to or afterremoval of the tertiary amide reaction vehicle from the neutralizedchlorination feed mixture. An aqueous solution of sucralose includingsalts and other compounds is produced, from which sucralose is recoveredby extraction and purified by crystallization. The resultant sucralosehas low levels of organic solvents.

BACKGROUND OF THE INVENTION

Selective modification of sucralose presents a major synthetic challengebecause of the multiplicity of reactive —OH groups and the acid labilityof the glycosidic linkage. When the target of interest is sucralose(4,1′, 6′-trichloro-4,1′,6′-trideoxygalactosuccrose: in the process ofmaking the compound, the stereo configuration at the 4 position isreversed; therefore, sucralose is a galacto-sucrose), the difficulty iscompounded by a need to chlorinate the less reactive 4- and1′-positions, while leaving intact the more reactive 6-position.

A number of different strategies for the preparation of sucralose havebeen developed to preblock the 6-position, usually by forming asucralose-6-acylate such as sucralose-6-acetate and removing theblocking moiety as by hydrolysis after chlorination to producesucralose. U.S. Pat. Nos. 4,950,746; 5,023,329; 5,034,551; 5,470,969;4,362,869; 4,826,962; 5,470,969; 5,530,106; and 4,980,473, which areexpressly incorporated by reference herein, relate to such strategies.

Prior to the isolation of pure sucralose, the sucralose-6-acylate isdesterified by hydrolysis. In one approach, the ester groups areconverted back to free hydroxyl groups by alkaline hydrolysis. After thehydrolysis, the feed mixture is adjusted to approximately neutral pH,and the sucralose is subsequently purified from the feed mixture by anyone of several acceptable processes. See, e.g., the U.S. patentapplications entitled “Extractive Methods for Purifying Sucralose” and“Process for Improving Sucralose Purity and Yield,” filed 8 Mar. 2002,and expressly incorporated by reference herein. The de-esterificationreaction may be carried in an organic system employing a material suchas sodium methoxide that produces a transesterification reaction. Inthis case, the acid moiety forming the sucralose ester is converted tothe methyl ester of the acid, whereby the methyl ester may be removed bydistillation, driving the reaction to completion. Alternatively, thede-esterification reaction may be carried out in water under alkalineconditions, resulting in a base-mediated conversion of ester tosucralose and the salt of the acid that was used to form the ester. Thelatter use of an aqueous hydrolysis is desirable because it avoids theuse of expensive solvents that must be removed during the laterpurification.

However, one problem with the latter sucralose purification strategy isthat sucralose in the de-esterified form is unstable under intenselyalkaline conditions and may be converted to undesirable compounds. Forexample, the anhydro compounds are undesirable because they decrease theoverall reaction yield, and they affect the sweetness properties ofsucralose. Hence, such undesirable compounds may also affect theduration of the extraction process. Moreover, high levels of suchmaterial greatly increase the difficulty of these purification steps.

The present invention provides processes whereby the acyl-sucralosecompound is deacylated directly to produce an aqueous solution ofsucralose including salts and other compounds, from which sucralose isrecovered and preferably then purified by counter-current extraction,crystallization, or a combination of such techniques.

Accordingly, the present invention provides a sucralose purificationprocess that produces sucralose compositions of enhanced purity and alsominimizes the overall loss of sucralose during the purification processprior to any specific extraction, while reducing the formation ofundesirable compounds such as anhydro sucralose.

SUMMARY OF THE INVENTION

The present invention provides a process for producing sucralose from afeed mixture comprising an acyl-sucralose compound in an aqueoussolution, whereby the process comprises (a) adjusting the pH of the feedmixture; (b) maintaining the feed mixture at an appropriate temperatureand time to effect the conversion of the acyl-sucralose compound intofree sucralose; (c) adding a buffer to the feed mixture of step (b) tostabilize the pH; (d) decreasing the pH of the feed mixture of step (b);and (e) recovering free sucralose.

In one embodiment of the present invention sucralose may be producedfrom a feed mixture comprising an acyl-sucralose compound in an aqueoussolution by adjusting the pH of the feed mixture to a range of about 8.0to about 12.0; maintaining the feed mixture at an appropriatetemperature for sufficient time to effect conversion of theacyl-sucralose compound into free sucralose; adding buffer to the feedmixture in an amount sufficient to stabilize the pH within the range forthe duration of the maintaining step; decreasing the pH of the feedmixture to about 4 to about 8; and recovering the sucralose. In aspecific embodiment, the pH of the feed mixture may be adjusted to about10.5.

In one embodiment of the present invention, the buffer may be an amine,amino acid, phenol, inorganic acid, saccharin, xanthine, hydroquinine,or a mixture thereof. In another embodiment of the present invention,the amine may be ammonia, alkylamines R—NH2, dialkylamines R1R2NH,trialkylamines R1R2 R3N, wherein the R, R1, R2, R3 are methyl, ethyl,1-propyl, 2-propyl, butyl, cyclohexyl, benzyl, pyrollidine or2-hydroxypyridine. In yet another embodiment of the present invention,the amino acid may be glycine, alanine, arginine, dimethylglycine,cysteine, or a mixture thereof. In one embodiment of the presentinvention, the phenol may be phenol or resorcinol. In anotherembodiment, the inorganic acid may be a carbonate. In a specificembodiment of the present invention, the buffer may be dimethylamine ora salt of dimethylamine.

In another embodiment of the present invention, the acyl-sucralosecompound may be6-O-acyl-4,1′,6′-trichloro-4,1′,6′-trideoxygalactosucrose. In yetanother embodiment, the6-O-acyl-4,1′,6′-trichloro-4,1′,6′-trideoxygalactosucrose compound maybe 6-O-acetyl-4,1′,6′-trichloro-4,1′,6′-trideoxygalactosucrose. In stillanother embodiment, the6-O-acyl-4,1′,6′-trichloro-4,1′,6′-trideoxygalactosucrose compound maybe 6-O-benzoyl-4,1′,6′-trichloro-4,1′,6′-trideoxygalactosucrose.

In an embodiment of the present invention, the feed mixture may besubstantially free of a tertiary amide. In another embodiment the feedmixture may be substantially free of dimethylformamide.

In one embodiment of the present invention, the recovered sucralose maycontain 20 ppm or less of an organic solvent. In this embodiment, theorganic solvent may be methanol, ethanol, methyl acetate, toluene,pyridine, DMF, dichloromethane, chloroform, or a mixture thereof. In oneembodiment, recovered sucralose may contain about 7 ppm or less ofmethanol. In another embodiment, recovered sucralose may contain about 7ppm or less of ethanol. In yet another embodiment, recovered sucralosemay contain about 10 ppm or less of methylacetate. In anotherembodiment, recovered sucralose may contain about 10 ppm or less oftoluene. In one embodiment, recovered sucralose may contain about 20 ppmor less of DMF. In another embodiment, recovered sucralose may containabout 10 ppb or less of dichloromethane. In still another embodiment,recovered sucralose may contain about 10 ppb or less of chloroform.

One embodiment of the present invention may comprise a composition ofmatter comprising sucralose, wherein the sucralose comprises 20 ppm orless of an organic solvent. In this embodiment, the organic solvent maybe methanol, ethanol, methyl acetate, toluene, pyridine, DMF,dichloromethane, chloroform, or a mixture thereof. In one embodiment,recovered sucralose may contain about 7 ppm or less of methanol. Inanother embodiment, recovered sucralose may contain about 7 ppm or lessof ethanol. In yet another embodiment, recovered sucralose may containabout 10 ppm or less of methylacetate. In another embodiment, recoveredsucralose may contain about 10 ppm or less of toluene. In oneembodiment, recovered sucralose may contain about 20 ppm or less of DMF.In another embodiment, recovered sucralose may contain about 10 ppb orless of dichloromethane. In still another embodiment, recoveredsucralose may contain about 10 ppb or less of chloroform. The presentinvention may also include a combination sweetener, a beverage, or aconsumer product combined with sucralose.

One embodiment of the present invention may comprise a sucralosecomposition, wherein the sucralose has been deacylated and may containabout 20 ppm or less of an organic solvent. In this embodiment, theorganic solvent may be methanol, ethanol, methyl acetate, toluene,pyridine, DMF, dichloromethane, chloroform, or a mixture thereof. In oneembodiment, recovered sucralose may contain about 7 ppm or less ofmethanol. In another embodiment, recovered sucralose may contain about 7ppm or less of ethanol. In yet another embodiment, recovered sucralosemay contain about 10 ppm or less of methylacetate. In anotherembodiment, recovered sucralose may contain about 10 ppm or less oftoluene. In one embodiment, recovered sucralose may contain about 20 ppmor less of DMF. In another embodiment, recovered sucralose may containabout 10 ppb or less of dichloromethane. In still another embodiment,recovered sucralose may contain about 10 ppb or less of chloroform. Thepresent invention may also include a combination sweetener, a beverage,or a consumer product combined with sucralose.

Other objectives, features and advantages of the present invention willbecome apparent from the following detailed description. The detaileddescription and the specific examples, although indicating specificembodiments of the invention, are provided by way of illustration only.Accordingly, the present invention also includes those various changesand modifications within the spirit and scope of the invention that maybecome apparent to those skilled in the art from this detaileddescription.

DETAILED DESCRIPTION OF THE INVENTION

It is understood that the present invention is not limited to theparticular methodologies, protocols, solvents, and reagents, etc.,described herein, as these may vary. It is also to be understood thatthe terminology used herein is used for the purpose of describingparticular embodiments only, and is not intended to limit the scope ofthe present invention. It must be noted that as used herein and in theappended claims, the singular forms “a,” an, and “the” include pluralreference unless the context clearly dictates otherwise. Thus, forexample, a reference to “a solvent” is a reference to one or moresolvents and includes equivalents thereof known to those skilled in theart and so forth.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of ordinary skillin the art to which this invention belongs. Numerous methods, devices,and materials are described herein, although any methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention. All documents cited hereinare incorporated by reference herein in their entirety.

Definitions

Batch operation as used herein describes a procedure in which a fixedamount of materials are introduced into a process, and the productsobtained from this fixed amount of input are recovered prior to theaddition of more input material.

Beverage as used herein includes any non-carbonated or carbonatedbeverage such as cola, diet cola, soda, diet soda, juice cocktail, rootbeer, birch beer, any fountain drink, sparkling fruit juice, water,sparkling water, tonic water, sport drink, fruit juices, isotonicbeverages and club soda. Beverage may also include any fermented ornon-fermented drink such as any beer, including ale, pilsner, lager, orderivation thereof, malt liquor, red wine, white wine, sparkling wine,fortified wine, wine cooler, wine spritzer, any pre-made cocktail mixerincluding margarita mix, sour mix, or daiquiri mix, any fermented fruitor tea beverage, hard liquor, and any flavored liqueur such as brandy,schnapps, bitters, or cordial. Beverage may include any liquid or drydairy, milk, or cream product or any liquid or dry dairy, cream, or milksubstitute such as half & half, non-dairy creamer, powdered creamer,flavored creamer, soy milk product, and lactose-reduced milk product andthe like. Beverage may also include any fruit or vegetable juice inwhole, concentrated, or powdered form and any combination of fruit andvegetable juices or other beverages. Beverage may also include coffee,any coffee drink, any coffee flavoring syrup, tea, iced tea, and cocoa,as well as any combination of any of the foregoing in powdered or liquidform. Beverage may also include powdered drink mixes of any flavors,including mixes requiring the addition of a sweetener before or afterreconstitution to fluid form.

Blocked sucralose as used herein refers to sucralose molecules on whichsome or all of the remaining hydroxyl groups have been blocked byesterification or other means.

Combination sweetener as used herein includes any combination orpermutation of sweeteners, including combinations of sucralose,saccharin, aspartame, acesulfame potassium, cyclamate, alitame, neotame,stevioside, glucose, fructose, levulose, maltose, lactose, any sugaralcohol, sorbitol, xylitol, and mannitol. Combination sweeteners may begranular in form, but may be in any other suitable form such as powder,liquid or syrup. The combination sweetener may consist essentially ofsucralose. The combination sweetener may consist essentially ofsucralose and a carrier such as dextrose, lactose, maltodextrin orwater.

Consumer product as used herein includes fruit products such asapplesauce, jams, jellies, marmalades, fruit snacks, fruit butters, andfruit spreads. Consumer product may also include any viscous or soliddairy, milk, or cream product, such as cheese, ice cream, ice milk,frozen yogurt, yogurt, and the like. Consumer product also includesbaked goods such as breads, doughnuts, cakes, cheesecakes, danishes,pastries, pies, bagels, cookies, scones, crackers, muffins, and wafers.Consumer product includes cereal products such as ready-to-eat coldcereals, grits, hot cereals, granola mixes, oatmeal, and trail mixes.Consumer product includes condiments such as butter, peanut butter,whipped cream, dulce de leche, sour cream, BBQ sauce, chili, syrup,gravy, mayonnaise, olives, seasonings, relish, pickles, sauces, snackdips, ketchup, salsa, mustard, salad dressings, and pickled peppers.Consumer product includes snack foods and confectionary products such asapple bars, pudding, candy bars, hard candy, chocolate products,lollipops, fruit chews, marshmallows, chewing gum, bubble gum, gummybears, jelly beans, caramel, taffy, pie fillings, syrups, gel snacks,mints, popcorn, chips, and pretzels. Consumer product includes meatproducts such as hot dogs, canned fish, sausage, prepared meats, cannedmeat, dehydrated meat, and luncheon meat. Consumer product includessoups, consommé, and bouillon. Consumer product includes dental productssuch as toothpaste, dental floss, mouthwash, denture adhesive, enamelwhitener, fluoride treatments, and oral care gels. Consumer productincludes cosmetic and beauty aids such as lipstick, lip balm, lip gloss,and petroleum jelly. Consumer product includes therapeutic items such asnon-tobacco snuff, tobacco substitutes, pharmaceutical compositions,chewable medications, cough syrups, throat sprays, throat lozenges,cough drops, antibacterial products, pill coatings, gel caplets, solublefiber preparations, antacids, tablet cores, rapidly absorbed liquidcompositions, stable foam compositions, rapidly disintegratingpharmaceutical dosage forms, beverage concentrates for medicinalpurposes, aqueous pharmaceutical suspensions, liquid concentratecompositions, and stabilized sorbic acid solutions, phosphate buffers,saline solutions, emulsions, non-aqueous pharmaceutical solvents(propylene glycol, polyethylene glycol, vegetable oils), aqueouspharmaceutical carriers (water, alcohol), and solid pharmaceuticalcarriers (lactose, cellulose), and pharmaceuticalpreservatives/additives (antimicrobials, antioxidants, chelating agents,inert gases, flavoring agents, coloring agents). Consumer productincludes nutritional products such as meal replacement bars, mealreplacement shakes, dietary supplements, protein mixes, protein bars,carbohydrate control bars, low carbohydrate bars, meal supplements,electrolyte solutions, whey protein products, metabolic responsemodifiers, appetite control beverages, and echinacea sprays. Consumerproduct includes animal foodstuffs such as dog and cat food, rat feed,cattle feed, pig feed, and bird feed. Consumer product includesfoodstuffs such as baby food, infant formulae, and other products forinfant health and nutrition, such as oral rehydration beverages.Consumer product includes tobacco products such as pipe tobacco,cigarette tobacco, and chewing tobacco. Consumer product includes anysubstance intended for oral consumption either alone or with anothersubstance. Consumer product includes any composition intended for oral,parenteral, intravenous, subcutaneous, intramuscular, intraorbital,intraspinal, intrasternal, or intraarterial administration to a human orother animal such as livestock or a domestic animal. A consumer productmay optionally include additional agents such as carriers (e.g., starch,lactose, and sucrose), bulking agents (e.g., maltodextrins), adjuvants(e.g., indocyanine green, vanilla, and oil of wintergreen), coloringagents, viscosity-adjusting agents including soluble cellulosederivatives (e.g., carboxy-methylcellulose), thickening gums (e.g.,xanthan, gellan, carrageenan), and synthetic food additive materials(e.g., polyoxyethylene, carbomer).

Continuous operation as used herein includes procedures in which productmay be removed from the process while input may be added; removal ofproduct or addition of input may be incremental, discontinuous, or at aconstant rate. Those skilled in the art will readily recognize that manyintermediate operations between pure batch operations and purecontinuous processes are possible. The embodiments of the presentinvention may be readily practiced by this full range of possibleoperations.

Crude sucralose as used herein includes sucralose mixed with otherchlorinated sugars, as well as sucralose and other chlorinated sugars onwhich some or all of the hydroxyl groups remaining after chlorinationmay have been blocked by esterification or other means known to thoseskilled in the art.

Crystallization as used herein includes processes in which a solution isrendered saturated or supersaturated with respect to a dissolvedcomponent, and the formation of crystals of this component is achieved.The initiation of crystal formation may be spontaneous, or it mayrequire the addition of seed crystals. As used herein, crystallizationalso describes the situation in which a solid or liquid material isdissolved in a solvent to yield a solution that is then renderedsaturated or supersaturated to obtain crystals. Also, included in theterm crystallization are the ancillary processes of washing the crystalswith one or more solvents, drying the crystals, and harvesting the finalproduct obtained.

Extraction operation as used herein includes procedures that may beperformed on a mother liquor to remove various compounds from the motherliquor. The specific operation may be selected from any number that maybe suitable for removing undesirable compounds. These operations mayinclude, but are not limited to, distillation, solvent extraction,chromatography, and derivatization followed by removal of thederivatized material.

Recycling of a mother liquor as used herein refers to the practice ofadding the mother liquor to another sucralose solution prior to, orduring, its crystallization. The mother liquor may be furtherconcentrated or purified prior to recycling. Recovery of a substantialportion of the sucralose remaining in this mother liquor may beessential to achieving an economically acceptable process yield.

Solvent as used herein includes a liquid that can dissolve anothersubstance.

In certain embodiments, “sucralose” may include compounds other thansucralose and includes products of any number of processes forsynthesizing sucralose that are not sucralose. These include anymonochloro-, dichloro-, tetrachloro-, and pentachloro-derivative ofsucrose and any other dissacharide derived from sucrose, as well as anytrichloro-derivative other than sucralose itself, whether present infree form or as esters of carboxylic acids. These include anyhalogenated sugar derivatives, such as dichlorosucrose acetate,6,1′,6′-trichlorosucrose, 4,6,6′-trichlorosucrose,4,1′,4′,6′-tetrachlorogalactotagatose,4,1′,6′-trichlorogalactosucrose-6-acetate,4,6,1′,6′-tetrachlorogalactosucrose, 4,1′-dichlorogalactosucrose,3′,6′-dichloroanhydrosucrose, 4,6′-dichlorogalactosucrose,1′,6′-dichlorosucrose, 6,6′-dichlorosucrose, 4,1′,6′-trichlorosucrose,4,6,6′-trichlorogalactosucrose,4,1′,5′-trichlorogalactosucrose-6-acetate, and4,6,6′-trichlorogalactosucrose and others as shown in U.S. Pat. Nos.4,405,654; 4,435,440; 4,980,463; 5,034,551; 5,498,709; and 5,530,106.These include any organic or inorganic salt, carbohydrate, or acylatedsucralose.

The present invention provides processes whereby acyl-sucralosecompounds are deacylated directly to produce an aqueous solution ofsucralose including salts and other compounds, from which sucralose isrecovered. Sucralose may then be recovered by extraction, for example byusing an organic solvent. The sucralose may then be purified bycounter-current extraction, crystallization or a combination of bothtechniques. In one embodiment, the present invention provides a processfor producing sucralose from a feed mixture comprising an acyl-sucralosecompound in an aqueous solution.

In one embodiment, the process of the present invention comprises: (a)adjusting the pH of the feed mixture to the range of about 8 to about11; (b) maintaining the feed mixture at an appropriate temperature andtime to effect conversion of the acyl-sucralose compound into freesucralose; (c) adding a buffer to the feed mixture in an amountsufficient to stabilize the pH; (d) decreasing the pH of the feedmixture to about 4 to 8; and (e) recovering the sucralose. These stepsmay be performed in any appropriate order.

In one embodiment, the process of the invention may employ a feedmixture that may contain di-, tri-, and tetra-chlorinated sucralosecompounds. U.S. Pat. No. 5,977,349, which is expressly incorporated byreference herein, relates to such mixtures and processes. In oneembodiment of the present invention, the acyl-sucralose compound maycomprise 6-O-acyl-4,1′,6′-trichloro-4,1′,6′-trideoxygalactosucroseesters. Further, the acyl-sucralose compound may comprise6-O-acetyl-4,1′,6′-trichloro-4,1′,6′-trideoxygalactosucrose or6-O-benzoyl-4,1′,6′-trichloro-4,1′,6′-trideoxygalactosucrose. The typesof halogenated compounds present in this feed mixture may vary accordingto the synthetic route used and the particular conditions of thesynthesis. Halogens suitable for use in the context of the presentinvention include bromine, chlorine fluorine, and iodine. One skilled inthe art may readily fill the various positions with the same halogen orwith any combination or permutation of different halogens by methodsknown to those skilled in the art.

In addition to the acyl-sucralose compound, the present invention mayemploy a feed mixture that comprises at least one additional componentselected from the group consisting of at least one other chlorinatedsucrose different from said first chlorinated sucrose, salt and solvent.U.S. Pat. No. 4,980,463, which is expressly incorporated herein byreference relates to feed mixtures that may be the neutralized reactionproduct of the acyl-sucralose and that are also employed to purifysucralose. In that embodiment, the feed mixture contains acyl-sucralose(such as sucralose-6-acetate or sucralose-6-benzoate), most likely atleast one other chlorinated sucrose (including esters thereof); thetertiary amide solvent for the chlorination reaction (preferablyN,N-dimethylformamide); various salt by-products of the chlorination andneutralization reaction (including alkali, alkali earth metal, ammonium,and alkyl ammonium chlorides, for example, sodium chloride anddimethylamine hydrochloride, as well as alkali metal formates, such assodium formate); and water.

Alternatively, the chlorination feed mixture can be subjected to steamstripping or the like to remove the tertiary amide solvent. U.S. Pat.No. 5,530,106, which is expressly incorporated herein by reference,relates to such processes. The removal of the tertiary amide may befollowed by hydrolysis to remove the 6-acyl moiety to produce anotherfeed mixture that can be used in the purification process of theinvention. In this embodiment, the feed mixture used in the process ofthis invention may contain sucralose; possibly other chlorinatedsucroses; various salt by-products of the chlorination andneutralization reaction (including alkali, alkali earth metal, ammoniumand alkyl ammonium chlorides, for example, sodium chloride anddimethylamine hydrochloride, as well as alkali metal formates, such assodium formate); water; less than about 1 or 2% by weight of the feedmixture of the tertiary amide solvent; and, some remainingsucrose-6-ester compounds (in an embodiment where the hydrolysis toremove the 6-acyl moiety was not complete).

On a laboratory scale, the crude chlorination product may be quenched ina batch operation by the addition (in one portion) of one molarequivalent (basis phosgene) of ice-cold aqueous solutions or slurries ofthe alkali or alkaline earth metal hydroxides. In one embodiment, thealkaline agents may include the hydroxides of sodium, potassium, andcalcium. In a specific embodiment, more dilute aqueous alkalinesolutions, such as about 3 to 4N sodium hydroxide, may be used. Broaderranges of concentration may also be used such as, about 2 to about 8Nsodium hydroxide. At lower concentrations, precipitation of salts isreduced or avoided, which significantly reduces the amount of solids theprocess stream can accommodate. However, when the concentration becomestoo low (e.g., below about 2N), the product stream may become diluted toan extent that may adversely affect the efficiency of the process.

In one method of practice of this quench method, a buffer may be addedto cold aqueous alkali with vigorous stirring as rapidly as possible ina quantity sufficient to raise and maintain the pH to about 8 to about10. The buffer of the present invention should provide protectionagainst abrupt changes in alkalinity or acidity. After addition of thebuffer, the solution may resist changes in pH when the solution isexposed to acids or alkalis that would otherwise cause dramatic changesin pH. In particular, the buffer of the present invention will maintainthe concentration of hydrogen ions, H⁺ at a fixed value.

In one embodiment of the present invention, the buffer shoulddemonstrate good buffering activity at a pH of about 10.5. Further, thebuffer should be capable of maintaining the pH of the solution within arange of 8 to 12.0. The addition of the buffer may prevent excursions ofpH to higher levels that may cause a related increase in the productionof undesired compounds. In an embodiment, other compounds may comprisethe formation anhydro compounds, such as3′,6′-anhydro-4,1′-dichlorogalactosucrose and1′,2,3′,6′-dianhydro-4-chlorogalactosucrose. Further, maintaining acloser control on the pH of the solution by the addition of buffer maystandardize the purity profile and result in an improved reproducibilityof the process of the present invention.

In one embodiment, the buffers of the present invention may include, butare not limited to, amines such as ammonia, alkylamines R—NH2,dialkylamines R1R2NH, trialkylamines R1R2R3N (where R, R1, R2,R3=methyl, ethyl, 1-propyl, 2-propyl, butyl, cyclohexyl, benzyl etc.,heterocycles such as pyrollidine, 2-hydroxypyridine, etc; amino acidssuch as glycine, alanine, arginine, dimethylglycine, cysteine; phenolssuch as phenol, resorcinol, etc.; inorganic acids such as carbonate, andother buffers such as saccharin, xanthine, hydroquinone, or a mixturethereof. In another embodiment of the present invention, a suitablebuffering agent may comprise dimethylamine or salts of dimethylamine.

After stirring several minutes at this mildly elevated pH, the quenchedsolution may be neutralized to pH 5-7 by the addition of an acid, suchas, for example, concentrated aqueous hydrochloric acid or glacialacetic acid. The brief treatment of the quenched chlorination feedmixture at pH 8-10 may have the beneficial effect of insuring that thehydroxyl groups of the sucrose-6-ester that have not been replaced bychlorine atoms are returned to their original hydroxyl group form.

In an alternative embodiment, sufficient aqueous alkali and bufferingagent may be added to attain a pH of 11 (^(±)1) and held for sufficienttime to remove the 6-acyl function and obtain sucralose in the presenceof all the salts, residual tertiary amide (DMF), etc. However, some DMFmay be lost by caustic hydrolysis to dimethylamine and sodium formate.For this reason, the deacylation prior to removal of DMF is lesspreferred, because it may be desirable to recover all the DMF forrecycle and re-use.

DMF Removal

When sodium hydroxide is used in the quench step and the tertiary amideis DMF, the salts such as sodium chloride, dimethylamine hydrochlorideand small amounts of sodium formate may be formed in the quench step. Ifthe quench is continued with a deacylation by increasing the pHsufficient to effect deacylation, the extraction of sucralose from thequenched and thus deacylated product mixture may be complicated by thepresence of DMF (or other tertiary amide) and the propensity of thetertiary amide to distribute between both organic and aqueous phases inthe extraction step, which may be the logical next step in a processsequence for producing sucralose. The tertiary amide may dissolvesucralose in both phases, and may also tend to dissolve other materialspresent in both phases, which may make recovery of the sucralose in goodyield difficult and/or expensive. Also, the presence of DMF or othertertiary amides may affect efficiency of sucralose purification bycrystallization from the extraction solvent. A further probablecomplication may be the base-catalyzed decomposition of the tertiaryamide. For all of these reasons, tertiary amides such as DMF arepreferably removed prior to recovery and purification of the sucralose.Further, it is preferred to remove the DMF prior to the deacylationstep.

For example, a steam stripping operation may be performed to remove amajor proportion of the DMF (or other tertiary amide) in the quenchedfeed mixture (preferred mode) or in the quenched and deacylated feedmixture. In one embodiment, it may be desirable to remove at least 95%,and in a specific embodiment, from at least about 98 to 99.9%, of theDMF to limit such undesirable consequences.

Upon removal of the DMF (or other tertiary amide) by steam stripping,the DMF may be effectively replaced with water in the process stream andthe DMF may be subsequently recovered from the aqueous overheads bydistillation and may be recycled.

Sucralose-6-Ester Deacylation

In one embodiment of the present invention, the sucralose-6-ester isdeacylated by increasing the pH of the feed mixture to about 11 (^(±)1)at a temperature and for a period of time sufficient to effect thedeacylation after removal of the tertiary amide. This step may beperformed by adding sufficient alkali metal hydroxide, such as sodiumhydroxide, with agitation, to increase the pH to the desired level. Inaddition, a buffering agent that demonstrates good buffering activity ofa pH of about 10.5 may be added. In one embodiment, reaction times andtemperatures within the range of about 30 minutes to 2 hours at about15° C. to about 35° C. may be used. At the conclusion of thedeacylation, the base present may be neutralized, as by addition ofhydrochloric acid, to a pH of about 5 to 7. After neutralization, theaqueous feed mixture may contain sucralose, salts (as above, plus thesalt produced by the neutralization step described immediately above),and other chlorinated sucrose byproducts.

Sucralose Extraction

Following deacylation, sucralose may be isolated by extraction of theaqueous brine solution with a variety of organic solvents. Thesesolvents include methyl acetate, ethyl acetate, methyl ethyl ketone,methyl iso-butyl ketone, methyl iso-amyl ketone, methylene chloride,chloroform, diethyl ether, methyl tert-butyl ether, and the like. U.S.patent application entitled “Extractive Methods for Purifying Sucralose”relates to such processes. In a specific embodiment, ethyl acetate maybe used for reasons of extraction selectivity, ease of recycle, andtoxicological safety.

Sucralose isolation may be performed in the laboratory by firstpartially evaporating the crude neutralized deacylation reactionproduct. About half the water present may optionally be removed,producing a solution containing about 2 to 5 wt % carbohydrates andabout 15 to 25 wt percent salts. Isolation may be performed by carryingout three sequential extractions with ethyl acetate or other appropriatesolvent. The extracts may be combined, and may optionally be washed withwater (to partially remove any residual DMF and dichlorodideoxysucrosederivatives that to some extent are partitioned into the organic phase).

In addition to the batch extraction technique outlined above, extractionmay also be carried out continuously on the dilute (not concentrated byevaporation) stream in a counter current mixersettler extraction system.The advantage is that no prior evaporation-concentration step isrequired. Such counter-current extraction techniques are known in theart.

Once the crude sucralose has been recovered from the aqueous brine as asolution in an appropriate organic solvent, it is concentrated and theproduct can be purified by crystallization and recrystallization fromthe same solvent until the required purity is achieved. U.S. patentapplication entitled “Process for Improving Sucralose Purity and Yield”relates to such processes. Alternatively, the sucralose may becrystallized from a solvent mixture such as methanol-ethyl acetate orfrom water to achieve the desired purity level. Sequential partitioningof the sucralose between solvent-water mixtures in a counter-currentmanner may also allow a purification to be achieved and likewise allowsa direct liquid fill process, i.e., no material isolation may be neededbecause the final process stream may have the requisite specificationsto be directly packaged for use.

Another embodiment of the purification/recovery process described aboveis that the same solvent may be used for both extraction andpurification steps. Typically, i.e., with other chemical materials, itis unlikely that the chemical product to be purified will crystallizefrom the same solvent that is used for extraction. In the present case,however, a combination of dilution and relatively low levels of othercompounds may allow the sucralose to remain in solution during theextraction, and then after the solution containing the extractedsucralose is concentrated, the sucralose product may then becrystallized from the same solvent.

Another aspect of the present invention relates to sucralose, producedvia the methods and processes disclosed herein, and including thedisclosed deacylation, crystallization and extraction techniques, whichcontains low levels of organic solvent. Such solvents may include, forexample, methanol, ethanol, methylacetate, toluene, pyridine, DMF,dichloromethane, chloroform, and any combination thereof. In a specificembodiment, levels of solvent in the sucralose may be less that 20 ppm.In particular, levels of methanol or ethanol may be 7 ppm or less. Inanother embodiment, levels of methylacetate, toluene, or pyridine may be10 ppm or less. In another embodiment, the level of DMF present in thesucralose may be 20 ppm or less. In still another embodiment, the levelof dichloromethane or chloroform in the sucralose may be 10 ppb or less.

The levels of such solvents in sucralose can be measured by knownmethods, such as gas chromatography for example, and as shown inTable 1. Organic solvents that may be tested include methanol, ethanol,methylacetate, toluene, pyridine, DMF, dichloromethane, chloroform or amixture thereof. TABLE 1 Organic Solvent Level Methanol 7 ppm Ethanol 7ppm Methylacetate 10 ppm Toluene 10 ppm Pyridine 10 ppm DMF 20 ppmDichloromethane 10 ppb Chloroform 10 ppb

The sucralose produced by the present invention may be used inbeverages, consumer products, combination sweeteners and other suchproducts.

EXAMPLES Example 1 Limiting Production of Anhydro Compounds withAddition of Buffering Agent

A solution containingacetyl-6-O-4,1′,6′-trichloro-4,1′,6′-trideoxygalactosucrose (or,6-acetyl ester) was prepared as related in U.S. Pat. No. 5,977,349,which is expressly incorporated by reference herein. Steam stripping wasemployed to remove any dimethylformamide remaining from the syntheticreaction. The feed mixture contained, in addition to the acetyl-6-ester,other chlorinated sucrose derivatives, residual N,N-dimethylformamide,salt byproducts of the chlorination and neutralization reactions,including alkali, ammonium, and alkyl ammonium chlorides. Sodiumchloride was a significant portion of the products, and dimethylaminehydrochloride was also present.

Sufficient aqueous sodium hydroxide was added to raise the pH of thefeed mixture to about 10.5. This pH was sufficient to facilitate thealkaline hydrolysis of the acetyl-6-ester. Concurrently with thecaustic, dimethylamine hydrochloride was added to provide buffercapacity to prevent an excessive increase in pH, which causes theformation of undesirable anhydro sucralose derivatives. The aboveconditions were sufficient to substantially convert the acetyl-6-esterto sucralose. A broad range of reaction conditions can be used to effectthis reaction.

1-22. (canceled)
 23. A composition comprising sucralose, wherein saidsucralose contains about 20 ppm or less of an organic solvent.
 24. Thecomposition of claim 23, wherein said an organic solvent is selectedfrom the group consisting of methanol, ethanol, methyl acetate, toluene,pyridine, DMF, dichloromethane, chloroform, and mixtures thereof. 25.The composition of claim 24, wherein said sucralose contains about 7 ppmor less of methanol.
 26. The composition of claim 24, wherein saidsucralose contains about 7 ppm or less of ethanol.
 27. The compositionof claim 24, wherein said sucralose contains about 10 ppm or less ofmethyl acetate.
 28. The composition of claim 24, wherein said sucralosecontains about 10 ppm or less of toluene.
 29. The composition of claim24, wherein said sucralose contains about 20 ppm or less of DMF.
 30. Thecomposition of claim 24, wherein said sucralose contains about 10 ppb orless of dichloromethane.
 31. The composition of claim 24, wherein saidsucralose contains about 10 ppb or less of chloroform.
 32. A combinationsweetener comprising the sucralose of claim
 24. 33. A beveragecomprising the sucralose of claim
 24. 34. A consumer product comprisingthe sucralose of claim
 24. 35. A composition comprising sucralose,wherein the sucralose is produced from a feed mixture comprising anacyl-sucralose compound in an aqueous solution by a process comprising:(a) adjusting the pH of said feed mixture to a range of about 8.0 toabout 12.0; (b) maintaining said feed mixture at an appropriatetemperature for sufficient time to effect conversion of saidacyl-sucralose compound into free sucralose; (d) decreasing said pH ofsaid feed mixture to about 4 to about 8; and (e) recovering thesucralose from the product of step (d); wherein the sucralose containsabout 20 ppm or less of an organic solvent.
 36. The composition of claim35, wherein said organic solvent is selected from the group consistingof methanol, ethanol, methyl acetate, toluene, pyridine, DMF,dichloromethane, chloroform, and mixture thereof.
 37. The composition ofclaim 36, wherein said sucralose contains about 7 ppm or less ofmethanol.
 38. The composition of claim 36, wherein said sucralosecontains about 7 ppm or less of ethanol.
 39. The composition of claim36, wherein said sucralose contains about 10 ppm or less of methylacetate.
 40. The composition of claim 36, wherein said sucralosecontains about 10 ppm or less of toluene.
 41. The composition of claim36, wherein said sucralose contains about 20 ppm or less of DMF.
 42. Thecomposition of claim 36, wherein said sucralose contains about 10 ppb orless of dichloromethane.
 43. The composition of claim 36, wherein saidsucralose contains about 10 ppb or less of chloroform.
 44. A combinationsweetener comprising the sucralose of claim
 36. 45. A beveragecomprising the sucralose of claim
 36. 46. A consumer product comprisingthe sucralose of claim 36.